Stem cell therapeutics is a promising field for tissue engineering and regeneration but it has shown limited success in repairing the central nervous system (CNS) and specifically the brain after severe injury. CNS injuries often cause extensive tissue damage characterized by neuronal and glial cell death where there is virtually no functional replacement of cells from the endogenous neural stem cells (NSCs). In an animal model of stroke, it was reported that less than 1% of the destroyed neurons are replaced from the endogenous neural precursors of the subventricular zone (SVZ). Similar results have been obtained in animal models of traumatic brain injury (TBI). Salman et al. (J Neurotrauma 21: 283-292, 2004) observed that neural precursors (NPs) from the SVZ repopulated a mechanically injured cortex. The SVZ cells proximal to the injured area produced a very small percentage of new neurons (not quantified), with the majority of the transplanted cells becoming astrocytes. Direct transplantation of NPs into the penumbra of brain lesions has yielded minor advancements (Sanberg et al., Br Med Bull 101: 163-181, 2012). Most of the transplanted cells either do not survive (Shindo et al., J Med Invest 53: 42-51, 2006) or differentiate into glial cells instead of neurons (Shear et al., Brain Res 1026: 11-22, 2004). Shear et al. (2004), for example, found that NG2 positive glial cells were produced upon transplanting NPs and Sun et al. (Exp Neurol 216: 56-65, 2011) observed that the majority of the precursors they transplanted became Olig2 positive cells (presumably glia). Ma et al. (Mol Med Rep 4: 849-856, 2011) reported that only 4% of NPs that they transplanted were NSCs, whereby only 11% differentiated into cells expressing a neuronal marker. Transplanting stem cells attached to a supportive matrix directly into the lesion site may be more effective in promoting regeneration. Tate et al. (J Tissue Eng Regen Med 3: 208-217, 2009) showed improvement in the long-term survival of NPs that were transplanted within a supportive fibronectin and laminin matrix after TBI. Animals receiving these transplants also showed improved performance in spatial learning tasks compared with injured mice that did not receive NPs (Tate et al., 2009).
Using principles from material engineering and molecular biology, tissue engineers are developing organic substitutes to support or replace portions of malfunctioning tissues or organs to create substitutes. The common approach to create these substitutes is to use living cells, scaffolding and signaling molecules. Evans (Semin Surg Oncol 19: 312-318, 2000) identified four components necessary for nervous tissue scaffolds: growth-promoting proteins, extracellular matrix (ECM), support cells (typically stem cells) and molecules that will promote axonal regeneration. However, stem cells require both contact with extracellular matrices as well as growth-promoting proteins to proliferate and retain the cardinal characteristics of stem cells (stemness). Extracellular matrix factors such as laminin and fibronectin, acting through integrin receptors, have been shown to be important for stem cell self-renewal. Of the growth growth-promoting proteins necessary for stimulating the proliferation of both embryonic and somatic stem cells, FGF-2 has been shown to be critical.
Traumatic injuries to the CNS are appropriate for the application of biomaterial scaffolds because there is extensive and localized loss of cells and ECM. A scaffold can serve as an artificial matrix and supportive network for engrafted cells as well as for the host tissue. Furthermore, it serves as both a physical and chemical barrier against glial scarring, which is well known to inhibit axonal regeneration. The ECM is also an important regulator of cell function. Interactions of ECM and integrins govern cellular processes such as proliferation, survival, migration and differentiation.
There is, therefore, a continuing need when designing regenerative therapies for neural tissue to develop biomaterial systems that mimic the native ECM. Such biomaterial systems should be designed in order to achieve a scaffold that is highly suitable as a vehicle for cell transplantation to repair traumatic brain injuries.